Accumulated hypertension burden on atrial fibrillation risk in diabetes mellitus: a nationwide population study

Background Patients with diabetes mellitus have an increased risk of incident atrial fibrillation (AF). The effect of accumulated hypertension burden is a less well-known modifiable risk factor. We explored the relationship between accumulated hypertension burden and incident AF in these patients. Methods We evaluated data for 526,384 patients with diabetes who underwent three consecutive health examinations, between 2009 and 2012, from the Korean National Health Insurance Service. Hypertension burden was calculated by assigning points to each stage of hypertension in each health examination: 1 for stage 1 hypertension (systolic blood pressure [SBP] 130–139 mmHg; diastolic blood pressure [DBP] 80–89 mmHg); 2 for stage 2 (SBP 140–159 mmHg and DBP 90–99 mmHg); and 3 for stage 3 (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg). Patients were categorized into 10 hypertensive burden groups (0–9). Groups 1–9 were then clustered into 1–3, 4–6, and 7–9. Results During a mean follow-up duration of 6.7 ± 1.7 years, AF was newly diagnosed in 18,561 (3.5%) patients. Compared to patients with hypertension burden 0, those with burden 1 to 9 showed a progressively increasing risk of incident AF: 6%, 11%, 16%, 24%, 28%, 41%, 46%, 57%, and 67% respectively. Clusters 1–3, 4–6, and 7–9 showed increased risks by 10%, 26%, and 45%, respectively, when compared to a hypertension burden of 0. Conclusions Accumulated hypertension burden was associated with an increased risk of incident AF in patients with diabetes. Strict BP control should be emphasized for these patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-023-01736-4.


Introduction
One in 11 adults has diabetes mellitus (DM) globally, and this population group is expected to rise to 700 million by 2045 [1,2]. Deaths due to DM have doubled since 1990 [3]. Cardiovascular disease is estimated to account for one-third of DM deaths, primarily due to coronary artery disease and stroke [4]. Thus, managing cardiovascular risk factors is essential in reducing the mortality and morbidity associated with DM.
Among patients with DM, the presence of hypertension or atrial fibrillation (AF) is associated with an increased risk of complications, including stroke [5,6]. Furthermore, the population with DM exhibits a higher risk of AF when compared to that without DM [7,8]. The combination of DM and hypertension has been associated with an up to three-fold increase in the prevalence of AF, compared to rates in people without DM [7]. One previous study proposed a predictive model for AF in patients with hypertension and DM with acceptable performance [9]. However, previous studies have primarily focused on the association between baseline hypertension and the incidence of AF [7][8][9]. The impact of accumulated hypertension burden on the risk of AF in patients with DM has not previously been explored.
In this study, we aimed to investigate the relationship between accumulated hypertension burden and incident AF in patients with DM using a large nationwide population-based cohort.

Methods
This study utilized the nationwide claims database of the Korean National Health Insurance Service (NHIS). The NHIS covers the entire South Korean population. The NHIS database consists of demographic variables, mortality data, medical expenses, diagnoses encoded by the International Classification of Disease, Tenth Revision of Clinical Modification (ICD-10-CM), utilization of inpatient and outpatient services, and prescription records [10]. Furthermore, the National Health Screening Program for chronic diseases targets people over the age of 19 and includes data on physical examinations, laboratory results, chest radiographs, and self-reported questionnaires [11].
This study was conducted in accordance with the Declaration of Helsinki. The data were anonymized, and thus, the study was exempted from the Institutional Review Board (IRB) review of Seoul National University Hospital (IRB no. E-2204-040-1314). In addition, because the data from the NHIS were de-identified, obtaining informed consent was not feasible. The use of the NHIS database from 2009 to 2012 was authorized in 2022.

Study population
An overview of the patient selection flow is depicted in Additional file 1: Figure S1. Patients with DM who underwent a National Health Insurance Corporation health examination between January 1, 2009, and December 31, 2012, were screened for the study (n = 2,746,078). Patients aged < 40 years (n = 191,249), and those with prevalent AF before enrollment were excluded. Patients who underwent three consecutive biannual health examinations, including the index health examination, were included (n = 550,044).

Definition of accumulated hypertension burden
During the health examination, a trained clinician measured the patient's brachial blood pressure (BP) with a sphygmomanometer or an oscillometer with an appropriate-sized cuff, with the patient in the sitting position, after at least 5 min of rest [12,13]. The BP measured at each health examination was classified into four categories: 'no hypertension' (systolic blood pressure (SBP) < 130 mmHg and diastolic blood pressure (DBP) < 80 mmHg); stage 1 hypertension (SBP 130-139 mmHg and DBP 80-89 mmHg); stage 2 hypertension (SBP 140-159 mmHg and 90-99 mmHg); and stage 3 hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg), consistent with previous hypertension guidelines [14,15]. We used the basic hypertension definitions from the 2017 ACC guideline for high BP and divided stage 2 hypertension into 2 groups: stage 2 (SBP 140-159 mmHg and 90-99 mmHg) and stage 3 (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg) for further detailed evaluation of hypertension burden.
To quantify hypertension burden, we used a semiquantitative scoring system for the BP measured at each health examination: 0 points for no hypertension, 1 point for stage 1 hypertension, 2 points for stage 2 hypertension, and 3 points for stage 3 hypertension. To estimate the accumulation of hypertension status, the above grouping was applied to three consecutively performed health examinations, and the points from each health examination were summed for each subject. As a result, the patients were categorized into 10 groups based on hypertension burden (0-9) after three consecutive health examinations. Groups 1 to 9 were regrouped into three clusters: 1' (1-3), 2' (4-6), and 3' (7-9), with group 0 as the reference group (Fig. 1). In additional statistical analysis, we selected subjects of SBP < 130 mmHg and DBP < 80 mmHg and assigned 0 point to normal BP (SBP < 120 mmHg and DBP < 80 mmHg) and 1 point to prehypertension (SBP < 130 mmHg and DBP < 80 mmHg). And the patients were categorized into 4 groups of 0-3.

Covariates
Baseline demographic information, comorbidities defined by ICD-10-CM codes, prescribed drug use (antihypertensive medication and anti-diabetic medication), and laboratory results from the health examination are described in Table 1. Detailed definitions of inclusion and exclusion criteria (AF, hypertension, DM), comorbidities (chronic kidney disease [CKD], dyslipidemia, heart failure, myocardial infarction [MI], stroke, chronic obstructive pulmonary disease), health behavior (smoking, alcohol consumption, regular exercise), and household income are listed in Additional file 1: Table S1. Use of anti-hypertensive medications (thiazide, loop diuretics, aldosterone antagonists, alpha-/beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers were reviewed). Use of anti-diabetic medications (sulfonylureas, metformin, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, and insulin) were noted. All covariates were evaluated at the last (index, third) health examination, with comorbidities assessed a year prior to the index health examination. General health examination values of SBP, DBP, body mass index, and waist circumference were used. Laboratory results consisted of estimated glomerular filtration rate (eGFR), fasting glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol [16].

Study outcomes and follow-up
During the follow-up period, the incidence of AF was assessed as the primary outcome. AF was defined as the diagnosis of related ICD-10-CM codes (I48; AF and atrial flutter) for the first time during at least two different outpatient clinic visits or admissions or death [17]. The index date was the last (third) health examination. Patients were followed from the index date until the incident AF, disqualification from the NHIS (immigration or death), or the end of the study (December 31, 2018), whichever came first.

Statistical analysis
For the baseline characteristics, continuous variables are presented as mean ± standard deviation (SD) and categorical variables as numbers and percentages. The comparison of baseline characteristics among different accumulated hypertension burden groups was performed with a linear trend test using a generalized linear model for continuous variables, the chi-square test, and the Cochran-Armitage trend test for categorical variables. The AF incidence rate (IR) was calculated by dividing the number of incident AF events by 1000 person-years at risk. For survival analysis, the Kaplan-Meier method and the log-rank test were used to determine the cumulative incidence of AF in relation to the accumulated hypertension burden. For multiple comparisons of Kaplan-Meier curve, Šidák correction was used. Cox proportional hazards regression models were used to evaluate the hazard ratio (HR) and 95% confidence interval (CI). Five stepwise Cox analysis models  Subgroup analyses were performed according to age (< 65 and ≥ 65 years), sex, the presence of CKD, prior MI or stroke, insulin usage, more than three oral antidiabetic medications, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, DM duration > 5 years, and antihypertensive medication, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB).
Statistical significance of p < 0.05 was used. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina, USA).

Hypertension burden clusters
In the four clusters, participants in the higher accumulated hypertension burden group were older, but the prevalence of comorbidities did not show a linear trend. A higher accumulated hypertension burden was associated with heavy alcohol consumption, less regular exercise, and a lower income. Those with a higher accumulated hypertension burden were also more likely to receive anti-hypertensive medications, although prescription of oral anti-diabetic medications or insulin and duration of DM > 5 years were less common. In addition, the higher accumulated hypertension burden group had higher mean BP, body mass index, and waist circumference at the index health examination. Laboratory results showed lower eGFR and higher fasting glucose, total cholesterol, and triglyceride levels in the clusters with higher hypertension burden.

Risk of incident AF according to accumulated hypertension burden
During a mean follow-up duration of 6.7 (SD 1.7) years, AF was newly diagnosed in 18,561 patients (3.5% of the total population; incidence rate of 5.3 per 1,000 personyears). Both IR and HR increased with increasing accumulated hypertension burden (Additional file 1: Tables S3 and S4, respectively). The cumulative incidence curves for AF according to the hypertension burden are shown in Fig. 2. Compared with patients with a hypertension burden of 0, those with a hypertension burden of 1 or higher showed a higher risk of AF.
Among the subjects with SBP < 130 mmHg and DBP < 80 mmHg, those who had prehypertension also showed an increased risk of AF compared to those who sustained normal BP (P = 0.0019) (Additional file 1: Table S5). Those who had BP at a range of prehypertension more than twice showed a similar risk to those who had prehypertension all the time (Additional file 1: Table S5, Figure S2).

Subgroup analysis
The results of subgroup analyses are presented in Table 2. AF incidence was higher in the subgroups of age > 65 years, CKD, prior MI or stroke, insulin use, DM duration > 5 years, and use of anti-hypertensive medication. The subgroup of patients with three or more oral anti-diabetic medications and insulin, considered to have more advanced DM, was consistent with the main results. The severity of DM, as presumed by the prescription of more than three oral anti-diabetic medications or insulin, did not show a significant interaction. The prescription of specific anti-diabetic medication (thiazolidinediones or dipeptidyl peptidase-4 inhibitors) and anti-hypertensive medication (ACEi/ARB) did not affect the risk of AF.

Discussion
In this study, our principal findings were as follows: (1) patients with DM with a higher accumulated hypertension burden had an increased risk of incident AF, and (2) accumulated hypertension burden showed a positive correlation with the risk of AF in a population with DM, regardless of the severity of DM. To the best of our knowledge, this is the first study to evaluate the risk of incident AF in patients with DM and an accumulated hypertension burden. DM is one of the most common chronic medical conditions, affecting one in 11 adults globally [1]. Patients with DM are at a higher risk of major cardiovascular adverse events and mortality compared to people without DM [18]. People with DM are more likely to develop AF by atrial structural remodeling and adrenergic activation and have an even higher risk of major coronary events, strokes, heart failure, and mortality when present in combination with AF [19][20][21]. DM patients with AF may also experience increased AF symptom burden and a lower quality of life [22]. Because cumulative exposure to DM status itself increases the risk of AF by 3% for each additional year [23,24], it is important to control other modifiable risk factors of AF in patients with DM.
Hypertension is a common modifiable risk factor that affects the pathogenesis, management, and prognosis of AF [25]. Hypertension is responsible for more than one-fifth of all incident AF and shows a linear increase in risk when the exposure is accumulated [12,26].
Hypertension affects more than two-thirds of patients with DM [27], and the coexistence of hypertension in patients with DM increases the risk of AF three-fold [7]. However, the latter study was a cross-sectional observational study that focused on the presence or absence of baseline hypertension [7]. The accumulated effect of hypertension on AF development in patients with DM has not been previously evaluated.
Although the pathophysiology of AF remains under investigation, there are possible explanations for the association between hypertension and AF. In animal models, hypertension is associated with atrial remodeling, especially fibrosis, and higher AF inducibility [25,28]. Longterm exposure to hypertension is also associated with left ventricular hypertrophy, leading to increased left atrial pressure and subsequent atrial enlargement [29,30]. Such structural remodeling leads to an increased incidence of AF in a dose-dependent response to cumulative hypertension burden, as shown in our study and by others [26]. As such, a change in left ventricular hypertrophy can be prevented or even improved with intensive BP control and anti-hypertensive medications [31,32], and strict BP control should lower the incidence of AF in patients with DM.
In the subgroup analyses, the patients with antihypertensive medication had a higher incidence of AF but the incidence was similar to those without antihypertensive medication, unlike the previous study conducted on the general population [26]. This difference could be caused by the effect of DM outweighing hypertension on the incidence of AF [7]. Another interesting result in the subgroup analyses was that the severity of DM, as determined by insulin usage [33], did not show a significant interaction with AF risk. Despite the increased absolute AF incidence in the insulin group (as was seen in previous study [34]), the accumulated hypertension burden had a similar impact on the risk of AF in patients with DM regardless of insulin usage. Thus, strict BP control is important in all patients with DM, irrespective of the severity of DM.
In this study, the accumulated hypertension burden persistently showed an increased AF risk regardless of the known duration of DM. Accumulated DM burden is known to be associated with an increased AF incidence [23]; therefore, a long-term comprehensive treatment plan for the evaluation and management of DM and hypertension is needed to lower AF risk in patients with longer DM duration. This is aligned with the current approach to characterization and evaluation of patients with AF [35], followed by a holistic or integrated care approach to AF management [36]. Such integrated care management has been associated with improved clinical outcomes [37] and is recommended in guidelines [38].

Study limitations
This study had several limitations. First, we used I48 to define AF. The use of ICD-10-CM codes in AF diagnosis may be less accurate than reviewing the actual electrocardiogram. However, the AF definition using I48 was previously validated using 628 patients with a positive predictive value as high as 94.1% [39]. There still is a possibility of underestimation of the actual AF incidence and surveillance bias on the contrary as well. Second, although this study used a health examination provided by the Korean National Health Insurance Cooperation, which covers at least 74% of the adults in Korea [40], the number of subjects with diabetes who went through three consecutive biannual health examinations was limited. Thus, the possibility of selection bias was inevitable in the

Conclusion
Among patients with DM, accumulated hypertension burden was associated with an increased risk of incident AF. Strict BP control should be emphasized in managing patients with DM to help reduce the risk of AF-related complications in this population.